For years, researchers have tried to determine how the defective gene in juvenile Batten disease leads to the seizures, mental impairment, and other symptoms of this devastating childhood disorder. A new study shows that mice lacking the gene that is altered, or mutated, in this disorder have an immune reaction that disables an important enzyme in the brain. The study also found signs of this reaction in children with Batten disease. The finding provides a new clue about how Batten disease may damage the nervous system and could lead to treatments for the disorder.

The study is the first to find evidence that the immune system plays a role in Batten disease. The immune attack inactivates an enzyme called glutamic acid decarboxylase 65 (GAD65) that normally converts one neurotransmitter called glutamate into another, called gamma-aminobutyric acid or GABA. The loss of the enzyme's activity leads to an excess of glutamate in the brain.

"The bottom line is that these children have an autoimmune response to a protein (GAD65) that is important for neurological function," says David A. Pearce, Ph.D., of the University of Rochester School of Medicine and Dentistry in New York, who led the study. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the June 1, 2002, issue of Human Molecular Genetics.*

Juvenile Batten disease is a fatal, inherited childhood neurodegenerative disorder that results from mutations in a gene called CLN3. Symptoms of this disorder usually appear between the ages of 5 and 10 and may include vision problems, seizures, personality and behavior changes, slow learning, or clumsiness. Over time, affected children suffer mental impairment, worsening seizures, and progressive loss of sight and motor skills. The disease is usually fatal by the late teens or twenties. Juvenile Batten disease is the most common of a group of disorders called neuronal ceroid lipofuscinoses, or NCLs. NCLs are characterized by a buildup of pigments called lipofuscins in the body's cells.

In the new study, Dr. Pearce and colleagues examined two strains of mice in which the CLN3 gene is disabled, or "knocked out." The CLN3 knockout mice develop symptoms that resemble those seen in human Batten disease. The researchers found an autoantibody (immune system protein) that inhibits GAD65 in the bloodstreams of these mice. Autoantibodies are generated when the immune system mistakenly begins attacking the body's own proteins. The mice also had elevated levels of glutamate, reduced GAD enzyme activity, and an abnormal condition called reactive astrocytosis in the brain. Reactive astrocytosis is a proliferation of star-shaped cells called astrocytes and typically occurs after the brain is damaged in some way. Gene analysis showed that the CLN3 knockout mice also had changes in the activity of several genes linked to the production and use of glutamate.

To see if children with Batten disease had an autoimmune reaction like the one seen in the mice, the researchers tested blood from 20 individuals with the disease. They found that all of the children with Batten disease had autoantibodies to GAD65, while children without the disease did not have this autoantibody. "We tested a lot of children with Batten disease, and all of them have this antibody, so it is clearly some sort of clue as to what's going on in this disease," says Dr. Pearce. Postmortem brain tissue from another child who died with juvenile Batten disease showed both reactive astrocytosis and reduced GAD levels compared to individuals without the disease.

"This is the first study to show autoimmunity in a pediatric neurodegenerative disorder of genetic origin," says Giovanna Spinella, M.D., a pediatric neurologist from NINDS. "The finding also illustrates how studying rare disorders can provide new ways of understanding disease processes that may be applicable in a broader sense."

Previous studies have shown that GABA-producing neurons are lost early in the course of Batten disease. Since these neurons frequently contain GAD65, their loss may result from the immune reaction to this enzyme. The excess of glutamate also may lead to neuron death through a process called excitotoxicity, in which neurons die because they become overstimulated. The resulting neuron loss may lead to the learning impairments, movement problems, and other neurological symptoms of Batten disease. Because the autoantibody prevents glutamate  which increases nerve signaling  from being converted to GABA  which inhibits neuron activity  the autoimmune reaction also provides a plausible explanation for the seizures that occur in children with Batten disease, says Dr. Pearce. Researchers believe that many seizure disorders result from neurotransmitter abnormalities that cause too much nerve signaling.

The researchers do not yet know how the lack of CLN3 causes the immune reaction, but they are planning additional studies to investigate that question. One possibility is that the loss of CLN3 may interfere with the function of GAD65 in a way that triggers the immune reaction, says Dr. Pearce.

Autoantibodies to GAD have been detected in three other human diseases: stiff person syndrome (SPS), cerebellar ataxia, and late-onset insulin-dependent diabetes mellitus (IDDM). The autoantibodies in SPS and cerebellar ataxia inhibit GAD activity, while those in IDDM do not. SPS and cerebellar ataxia are adult-onset neurological disorders that cause progressive muscle rigidity and spasms, symptoms that also occur in the late stages of Batten disease. A recently reported clinical trial by NINDS researchers found that immunotherapy significantly decreased stiffness and spasms in patients with SPS. Since juvenile Batten disease is linked to the same type of autoimmune response as SPS, immunotherapy may help to slow the progression of Batten disease, says Dr. Pearce.

While the new findings are intriguing, more research is needed to determine what the loss of the CLN3 gene does in the body and how the autoimmune response may contribute to the symptoms and progression of juvenile Batten disease, says Dr. Pearce. He and his colleagues are planning studies to investigate these questions.

The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system.